One of the most significant health problems is the inadequate control of pain, especially chronic pain that is associated with many diseases such as cancer, back pain, arthritis, diabetic neuropathy, and other conditions. Postoperative pain affects up to 53 M patients in the United States alone. Despite most patients receiving some form of pain management, over half of these patients still experience inadequate pain relief. It is estimated that annual cost for health care and lost productivity related to pain is over $100 billion dollars in the United States. Impact of pain to society can be measured not only in economic numbers, but more importantly also by the patients' suffering. More than 50 million Americans live partially or totally disabled by chronic pain. There is currently no nationally accepted consensus for the treatment of chronic pain not due to cancer, yet the economic and social costs of chronic pain are substantial, with estimates ranging in the tens of billions of dollars annually. Although other areas of the world may have different protocols for pain relief, pain is a universal problem.
Morphine and other opioids have been widely used clinically for the treatment of pain. Tolerance including attenuated analgesic effect after repeated administration of opioids is well documented in clinical practice and causes inadequate treatment of pain. Pharmacological studies have established that morphine-induced analgesia, tolerance, and dependence are primarily mediated by mu opioid receptors (MOR). There have been many potential targets proposed to alleviate tolerance but many targets are intracellular. In addition, achieving cell-specific delivery presents a challenge to traditional pharmacological approach.
Opioid analgesics and traditional NSAIDs remain a mainstay of pain treatment; however, use of opioids for chronic pain leads to development of drug tolerance and drug dependence. The publications endorsed by AAPM and APS state that opioids sometimes called “narcotic analgesics,” are an essential part of a pain management plan.
Impediments to the use of opioids include concerns about addiction, respiratory depression and other side effects, tolerance, diversion, and fear of regulatory action.
Opioid addiction has physiological (sudden absence of the drug produces a withdrawal syndrome) and psychological components (the urge to use opioids to achieve euphoria, sedation and the like). Dependence is the term referring to physiological response at withdrawal. A decreased responsiveness to the pharmacological effects of a drug resulting from previous exposure is called tolerance.
There are cellular opioid receptor subtypes. In general an opioid reacts with all receptor subtypes in some way. The following basic principle holds since the binding of an opioid to the different receptor populations is variable, the affinity of an opioid to a subtype of receptor manifests itself in the dependant clinical effects.
ReceptorFunctionμκδAnalgesia cerebral+−+Spinal+++Vigilance−↓↑Respiratory drive↓−↑Heart rate↓↑Cardiovascular tonus−↓−Endorcrine effects+−−Diuresis↓↑−Constipation+−−Euphoria+−−Dysphoria−++Pupil size↓↓↑Nausea+−+Muscular rigidity↑↓↑− = no effect, + = effect, ↑ = increasing, ↓ = decreasing
Finding a method and/or agent to prevent and/or reverse opioid tolerance would provide better pain control in a large population of patients who are not adequately treated with opioid analgesics alone. Such a method/agent will also have use in treating opioid addiction.
Many cellular pathways (including several studied in the inventor's lab) have been proposed to stop opioid tolerance and/opioid dependence. However, most of these pathways have not been developed into medications that can help patients, most commonly due to the following reasons:                the targets are intra-cellular making bioavailability a difficult issue to overcome for potential drugs;        most targets are ubiquitously expressed therefore inhibiting such targets may produce too many unnecessary side effects; and        some of the most selective inhibitors for these intracellular pathways are peptides, making delivery to the target especially difficult.        
New compounds boasting novel modes of delivery are desperately needed in this developing market.